One possible mechanism leading to the dysfunction and cell loss in Huntington's disease (HD) is deficient neurotrophic support. In this application, we will investigate the role of brain derived neurotrophic factor (BDNF) signaling via its TrkB tyrosine kinase receptor in the survival, maintenance, development, and function of different neuronal populations in the striatum. In HD, the neurons of 'indirect pathway' that co-expresses D2 dopamine receptor and enkephalin (D2/Enk) are affected earlier and more severely in the pathological course of the disease. Our preliminary data prompt us to hypothesize that selective vulnerability of D2/Enk neurons in HD might be due to the preferential expression of the TrkB receptors on these neurons. To prove this hypothesis we will use BAG D2-EGFP transgenic mouse line and cross it to the striatum-specific trkB mutant. D2-EGFP mice can serve as an invaluable tool in looking at the alterations occurring in this striatal population in the absence of TrkB signaling. Changes in the cell number, morphology, and function specific to D2/enkephalin expressing neurons will be examined and compared to other striatal populations using specific neuronal markers. To display elements of cytoarchitecture we will label neurons using Golgi impregnation and a fluorescent dye. In situ hybridization, Western blotting, and immunohistochemistry will be employed to analyze changes in the expression pattern in different neuronal subsets of the striatum. Whole-cell patch-clamp recordings in the live cortico-striatal slices will allow us to examine specific changes in the synaptic transmission and plasticity. This data could provide a link between striatal dysfunction and motor symptoms observed in HD patients. Relevance: It is important to understand molecular basis of selective neuronal degeneration observed in patients with Huntington's disease. Elucidating the role of Brain Derived Neurotrophic Factor and its TrkB receptor in the pathogenesis of this fatal genetic movement disorder can be critical for finding novel therapeutic agents that can protect affected neurons from dysfunction and cell death. [unreadable] [unreadable] [unreadable]